Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, 171 64, Stockholm, Sweden.
Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden.
Acta Neuropathol Commun. 2024 Mar 1;12(1):37. doi: 10.1186/s40478-024-01724-z.
Leber's hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.
Leber 遗传性视神经病变（LHON）由影响复合物 I 的 mtDNA 突变驱动，表现为进行性视网膜神经节细胞功能障碍，通常没有眼外症状。目前尚无针对 LHON 的长期神经保护剂。口服烟酰胺对其他视网膜损伤中的线粒体和代谢功能障碍具有强大的神经保护作用。我们通过在老鼠眼睛内注射复合物 I 抑制剂鱼藤酮来模拟 LHON，探索烟酰胺保护 LHON 中线粒体的潜力。利用在视网膜神经节细胞中表达线粒体标记物 YFP 的 MitoV 老鼠，我们通过超分辨率成像和数字重建来评估线粒体形态。鱼藤酮诱导的复合物 I 抑制导致视网膜神经节细胞广泛的线粒体损失和碎片化。这一现象可以通过口服烟酰胺治疗来预防。过渡电子显微镜定量分析线粒体超微结构，表明鱼藤酮注射后嵴密度降低，烟酰胺治疗也可以预防这种情况。这些结果表明，烟酰胺在复合物 I 功能障碍期间保护线粒体。烟酰胺有可能成为治疗 LHON 的有效策略，以限制视网膜神经节细胞变性。
